Apoptosis is a genetically programmed and physiologically important form of cell death. It is a conserved cellular homeostatic mechanism with important roles in normal development through maintaining of cell turn-over in healthy adult tissues. Abnormal apoptotic activity has been linked to the pathogenesis of autoimmune and infectious disorders, including persistent inflammatory diseases (Gyrd-Hansen, et al., Nat Rev Cancer 10(8) 561-74). Evading apoptosis has also been identified as a hallmark of cancer (Hanahan D., et al., Cell 2000, 100(1), 57-70). Therefore, triggering apoptotic processes may be important for killing cancer cells and sensitizing them to different therapeutic regimens (Ashkenazi, A., Nat Rev Drug Discov 2008, 7(12), 1001-12; Ashkenazi, A, et al., J Clin Invest 1999, 104(2), 155-62).
Among promising candidates for cancer therapeutics is tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) initiated apoptosis through the receptor-mediated mechanism, also referred to as the extrinsic apoptotic pathway. In contrast to the naturally occurring pro-apoptotic ligands such as TNF and Fax ligand (FasL), TRAIL infusion into mice does not cause a lethal response or detectable toxicity to tissues and organs (Ashkenazi, A., Nat Rev Drug Discov 2008, 7(12), 1001-12; Ashkenazi, A, et al., J Clin Invest 1999, 104(2), 155-62; Walczak, H. et al., Nat Med 1999, 5(2), 157-63). Furthermore, the potential significance of TRAIL for killing cancer cells has been supported by studies in animal models demonstrating that this cytokine possesses selective toxicity to human tumor xenografts but not normal tissues. However, sensitivity to TRAIL-induced apoptosis is a key factor limiting the efficacy of TRAIL treatment, because a spectrum of sensitivity is observed in different malignant cells (Lippa, M. S. et al., Apoptosis 2007, 12(8), 1465). Furthermore, similar to normal cells, some cancer cells are also resistant to TRAIL-induced apoptosis.
The increasing understanding of the molecular details of apoptosis indicates that tumor cells can acquire resistance to apoptosis through interference with either extrinsic or intrinsic apoptotic signaling pathways. However, most cancer cells retain the capacity to undergo apoptosis if triggered through mechanisms that can overcome anti-apoptotic influences. For example, inhibition of NF-κB activity significantly increases apoptosis induced by apoptotic stimuli (Beg. A. A., et al, Science 1996, 274 (5288), 782-4; Wang, C. Y., et al., Science 1996, 274 (5288), 784-7; Van Antwerp, D. J., et al., Science 1996, 274 (5288), 787-9; Liu, Z. G., et al., Cell 1996, 87(3), 565-76). In addition, enhancing apoptosis also occurs upon activation of several intracellular non-apoptotic signaling processes, including the JNK pathway or endoplasmic reticular (ER) stress, known in eukaryotic cells as the unfolded protein response (UPR) (Ron, D. et al., Nat Rev Mol Cell Biol 2007, 8(7), 519-29). It has been observed that UPR activators such as tunicamycin, thapsigargin and RRR-α-tocopherol ether-link acetic acid analog (α-TEA), senstivize cancer cells to TRAIL-inducing apoptosis (Jiang, C. C., et al., Cancer Res 2007, 67(12), 5880; Chen, L. H. et al., Carcinogenesis 2007, 28(11), 2328-36; Tiwary, R., et al., PLoS One 5(7), e11865). However, these reagents induce constitutive and sustained activation of the UPR.
Bacterial metabolites play important roles in inflammation-mediated processes essential for normal development and the pathogenesis of numerous chronic diseases, including cancer. Inflammation is typically initiated as an innate immune response to specific bacterial products through receptor-dependent mechanisms, in which induction of the transcription factor NF-κB is required for both activation of the immune system and the control of apoptosis in activated cells. For example, in the presence of Gram-negative bacteria, NF-κB activation is initially induced in response to bacterial lipopolysaccharide (LPS), an agonist of the Toll-like receptor 4 (TLR4), leading to the expression of NF-κB-regulated genes encoding pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF) and interlekin-1 (IL-1). After the engagement of TNF or IL-1 receptors, additional rounds of NF-κB activation amplify this LPS-induced inflammatory response. NF-κB-dependent processes, in concert with other signaling pathways, up-regulate the expression of pro-apoptotic cancer immunosurveillance effectors, including the TNF-related apoptosis-inducing ligand (TRAIL), an essential mediator of apoptotic cell death particularly in cancer cells. Although the LPS-induced inflammatory response results in the release of pro-apoptotic cytokines such as TNF and TRAIL, cancer cells receiving these death signals can still survive due to the suppressive effects of NF-κB signaling on apoptosis.